Summary: Chronic kidney disease (CKD) is a common disease affecting >15% of the US adult population and has cardiovascular mortality10- to 30-folds greater than that in general population. We recently discovered a novel inflammatory monocyte subset the CD40 monocyte (MC) that has strong inflammatory feature and is elevated in CKD patients. We determined CD40+ MC as a novel inflammatory MC subset which is elevated in CKD subjects. Additional preliminary data lead us to hypothesize that CKD and uremic toxins induce CD40+ inflammatory MC differentiation via CD40 ligand induced CD40 expression, DNA hypomethylation on CD40 promoter, and 2) CD40 Inhibition, inflammasome suppression and DNA methylation therapy can reverse CD40+ MC differentiation, vascular inflammation and atherosclerosis. We will test this hypothesis using three connected Aims. Aim 1 will investigate the effect of CKD on CD40+ MC differentiation and tissue inflammation in human and mouse models of CKD, and in uremic toxin-treated human/mouse PBMC. Aim 2 will examine molecular mechanism underlying CKD-induced CD40+ MC differentiation. Aim 3 will test the therapeutic benefit of CD40 blocking, Casp1 inhibition and DNA methylation on CD40+ MC differentiation, atherosclerosis and kidney function in CKD. Accomplishment of the proposed research will lead to the identification of fundamental mechanistic links between CKD and cardiovascular disease, and novel therapeutic targets.